ABIM • PCCULesson 10, Volume 12—Asthma: Evolving Anti-Inflammatory TherapyLewis J. Smith, MD, FCCP; and Peter H.S. Sporn, MD, FCCP Objectives
Key wordsairway inflammation; anti-inflammatory therapy; corticosteroids; leukotrienes; T-lymphocytes Previously, asthma was considered a disease of airway smooth muscle that was characterized by increased contractility in response to a wide range of bronchoconstricting stimuli.1 However, recent studies indicate that the airway narrowing seen in patients with asthma is not solely the result of airway smooth muscle contraction. Other factors which contribute to airway narrowing include increased vascular permeability with edema of airway walls, infiltration of the airways with inflammatory cells, and mucus hypersecretion with plugging of smaller airways.2 These inflammatory components of asthma resolve only slowly, and respond poorly to bronchodilators such as b-agonists. There is now general agreement that inflammation is a key component of asthma, and therapy should address this inflammatory component. Indeed, recent guidelines for the management of asthma stress the importance of anti-inflammatory therapy for patients with nearly all degrees of asthma severity.2 This approach to management is a far cry from when bronchodilators were the mainstay of asthma therapy and corticosteroids were used only for patients with the most severe disease. The inflammation characterizing asthma is complex and involves multiple cells and mediators. The cells involved include well-recognized immune and inflammatory cells—lymphocytes, macrophages, eosinophils, mast cells, and neutrophils—as well as resident lung cells not traditionally considered to have inflammatory potential, such as airway epithelial cells and vascular endothelial cells3 (Figure 1). The products of these cells include cytokines such as interleukin (IL)-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, granulocyte-macrophage colony stimulating factor (GM-CSF), tumor necrosis factor-a (TNF-a), and transforming growth factor-b (TGF-b); reactive oxygen species such as superoxide anion, hydrogen peroxide, hydroxyl radical, and peroxynitrite; preformed granular products such as eosinophil major basic protein, eosinophil cationic protein, histamine, and mast cell tryptase; lipid mediators including prostaglandins, leukotrienes, and platelet-activating factor; and adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and selectins. Although space limitations do not permit a detailed description of each of the cells, their products and the interactions between them, CD4+ T lymphocytes appear to play a key role in orchestrating asthmatic airway inflammation. Among T-cell products, IL-4 promotes B cell differentiation and IgE synthesis, and IL-5 stimulates differentiation, chemotaxis, and activation of eosinophils. Figure 1. Schematic diagram of the cell and cytokine interactions in asthmatic inflammation and some of the bioactive mediators released from the inflammatory cells.
Although these cell products have unique properties, there is substantial redundancy in the system. The success achieved with corticosteroids is believed to be due, at least in part, to their ability to inhibit or down-regulate multiple components of the inflammatory cascade. The lack of effect of the more potent antihistamines and the poor results with the first-generation antileukotrienes suggested that blocking only one of the many mediators or pathways was unlikely to produce clinically important benefits. However, recent results with the newer antileukotriene drugs indicate that clinically significant and meaningful benefits can be achieved by blocking the action or synthesis of a single component of this complex inflammatory process. The positive results with the antileukotrienes also provide a strong incentive for evaluating new drugs which target other specific components of the inflammatory cascade. Although it is unlikely all of the new therapeutic approaches being taken and planned will be successful, it can be anticipated there will be beneficial effects from at least some of them. Further, as with studies testing the safety and efficacy of the antileukotrienes, one important result will be additional insight into the pathobiology of asthma. What follows is our perspective on evolving anti-inflammatory therapy for asthma. CorticosteroidsWith the exception of rare cases, corticosteroids are extremely effective treatment for asthma. In fact, they are the most uniformly effective therapy currently available. The introduction of inhaled corticosteroids, along with the development of improved delivery devices such as spacers and dry powder inhalers, has improved efficacy, reduced local side effects, and has resulted in a more favorable therapeutic-to-toxic ratio. Although high doses (>1000 µg) of inhaled corticosteroid given for prolonged periods of time can produce adverse systemic effects in adults, the toxicity is modest compared to that seen with equally effective doses of systemically administered corticosteroids. Corticosteroids produce their beneficial effects in a number of ways. For example, they increase b-adrenergic receptors and decrease the expression of several pro-inflammatory cytokines (eg, IL-1, IL-8, RANTES, GM-CSF), lipid mediators and adhesion molecules.4 Recent data indicate that corticosteroids act by regulating nuclear transcription factors (eg, nuclear transcription factor kappa B and activator protein-1) which control expression of genes for cytokines and enzymes involved in synthesis of several key inflammatory mediators. Interestingly, leukotriene synthesis is poorly inhibited by corticosteroids in some in vitro systems, an observation with potential therapeutic implications discussed below. Extensive clinical experience with inhaled corticosteroids in moderate and severe asthma led to studies exploring their usefulness in patients with very mild disease, a group traditionally treated with bronchodilators alone or bronchodilators plus either theophylline or a cromone. In a 2-year study performed in patients with mild asthma of recent onset (initial FEV1 87% of predicted), the inhaled corticosteroid budesonide improved pulmonary function and symptoms and decreased airway reactivity.5 These beneficial effects were not seen when b-agonists were used alone. After the initial study period ended, patients who had not received budesonide were started on the inhaled corticosteroid at the same dose (1200 µg/day) and were followed over time. The individuals not treated with budesonide for the first 2 years of the study did not achieve the same degree of improvement in lung function and symptoms and decrease in airway reactivity as those who received the inhaled corticosteroid from the beginning of the study, ie, earlier in the course of their disease.6 Nearly all of the patients who improved while receiving inhaled corticosteroids for the initial 2 years maintained that improvement after the dose was reduced by two-thirds, and some continued to do well even after discontinuing corticosteroid treatment altogether. These studies and others provide support for the current recommendation that inhaled corticosteroids, or another equally effective and safe anti-inflammatory therapy, be used in asthmatics with nearly all degrees of disease severity. Consideration also should be given to initiating therapy as early as possible after the diagnosis is made. CromonesThe cromones (cromolyn sodium, nedocromil sodium) are generally less effective than inhaled corticosteroids. However, they are used for the treatment of asthma, especially in children, because of the absence of significant side effects. Their beneficial effects were initially thought to be due to inhibition of mast cell mediator release, but it is now recognized that they can influence other inflammatory cells and sensory nerves. Recent information suggests that the cromones influence chloride channels expressed on sensory nerves, mast cells, and possibly other inflammatory cells, and this contributes to their therapeutic efficacy.7 The chromones are of variable and unpredictable effectiveness, especially in adults. This observation and others (see the antileukotrienes below) support the notion that asthma is a heterogeneous disease in which various underlying defects produce similar pathophysiologic abnormalities. Phosphodiesterase InhibitorsAdenosine 3',5'-cyclic monophosphate (cyclic AMP) has multiple biological actions which may be beneficial in patients with asthma. It dilates bronchial smooth muscle, induces apoptosis of lymphocytes and eosinophils, and blocks a variety of inflammatory responses.8 Theophylline, which inhibits phosphodiesterase and thereby increases cyclic AMP, has been used for decades to treat asthma. However, its use has been limited by its relatively weak bronchodilator and anti-inflammatory activity, a narrow therapeutic-to-toxic ratio, the availability of potent short- and long-acting inhaled b2-agonists, increasing use of inhaled corticosteroids, and more recently the development of new drugs such as the antileukotrienes (see below). Recent studies have identified at least seven phosphodiesterase (PDE) isoenzymes, some with several splice variants. Work in this area has focused on finding inhibitors of the isoenzyme(s) most relevant to asthma, with less toxicity than theophylline. Inhibitors of PDE IV have received the greatest attention because PDE IV appears to be the predominant isoenzyme in neutrophils and eosinophils, is also found in mast cells and airway epithelium, and may contribute to superoxide anion generation. Selective PDE IV inhibitors are bronchodilators, and they inhibit lymphocyte proliferation and cytokine release. Although PDE IV inhibitors may prove to be effective in the treatment of asthma, it is presently unclear whether a selective isoenzyme inhibitor will be more effective and safer than theophylline for treating asthma. AntileukotrienesMore than 50 years ago a factor was identified in antigen-sensitized guinea-pig lungs that produced slow, prolonged contraction of smooth muscle. This material was called slow-reacting substance of anaphylaxis (SRS-A). The physiologic properties of SRS-A were characterized over the years, and in the late 1970s SRS-A was shown to consist of the cysteinyl leukotrienes (LTC4, LTD4, LTE4). These leukotrienes are metabolites of arachidonic acid, a polyunsaturated fatty acid that is widely distributed in cell membrane phospholipids. The synthesis of the leukotrienes requires an active phospholipase A2 to release the arachidonic acid, 5-lipoxygenase (5-LO) and 5-lipoxygenase activating protein (FLAP) to generate LTA4, and LTC4 synthase to generate LTC4 by joining glutathione, a tripeptide containing cysteine, to LTA4. Peptidases then remove one of glutathione's amino acids to generate LTD4, and a second amino acid to produce LTE4. Additional information about leukotriene synthesis and its physiologic properties is available in a recent review.9 Several studies have shown that, when inhaled, the cysteinyl leukotrienes can reproduce the key features of asthma, including bronchoconstriction, airway hyperreactivity and inflammatory cell influx into the lung. The cysteinyl leukotrienes are synthesized by inflammatory cells believed to play an important role in asthma, including eosinophils and mast cells. They are also found in lung lavage fluid after challenge with antigen and in urine (LTE4) after antigen challenge and during acute asthma attacks. Further, several leukotriene receptor antagonists and synthesis inhibitors are effective in treating patients with asthma. Some of the compounds currently in use or under investigation are shown in Table 1.
Several large multicenter trials using either a leukotriene receptor antagonist or a leukotriene synthesis inhibitor have been performed, and some of them have been published (Table 2). Patients with mild-to-moderate asthma treated with antileukotriene drugs have consistently shown a 10 to 15% increase in FEV1 and peak expiratory flow rate (PEFR), and a 25 to 50% decrease in nocturnal awakenings, symptom scores, b-agonist use and asthma exacerbations as compared to placebo. There is less information about the effectiveness of these drugs in patients already receiving inhaled or systemic corticosteroids. Preliminary results indicate that the antileukotrienes provide additional beneficial effects and may permit a reduction in corticosteroid dose. These findings are consistent with in vitro studies which have shown that corticosteroids have limited inhibitory effects on production of mast cell mediators, including leukotrienes, and a recent report that corticosteroids actually increase 5-LO and FLAP mRNA and protein in a monocyte-like cell line.
As there has been limited experience with these drugs, their toxicity may not be fully defined. Initial results with the leukotriene receptor antagonist zafirlukast, and probably pranlukast and montelukast, have revealed a side effect profile similar to that seen in placebo-treated patients. In contrast, the 5-LO inhibitor, zileuton, has some liver toxicity which may be seen as an increase in transaminases. The incidence of liver function abnormalities is about twice that seen with placebo-treated patients. Current recommendations are that patients given zileuton have liver function tests performed before starting treatment, monthly for the first 3 months, and less frequently thereafter. It is important to put the toxicity and monitoring guidelines in perspective. Similar abnormalities of liver function were found and monitoring was recommended when the HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase cholesterol lowering drugs were approved for use. Experience with them has been quite good and toxicity is limited. A major issue at this time is in whom and when to use these new antileukotriene drugs. Except for patients with aspirin-sensitive asthma who respond very well to the antileukotrienes, there are presently no clinical or laboratory features that identify those patients most likely to benefit from these new drugs. In clinical trials, the responses to antileukotriene therapy have been heterogeneous—some patients have had dramatic beneficial effects and others have not improved at all, while the majority have demonstrated a modest benefit. Further, most of the large clinical studies have been performed in patients with mild-to-moderate disease, yet these drugs have been successfully used in patients with more severe disease as well. At this time one can only advise a trial and error approach, a situation typical of the use of most new therapies in medicine. More specific recommendations should be possible as experience is gained. MethotrexateMethotrexate, a folic acid analogue used at high doses as an antimetabolite cancer chemotherapeutic agent, also has anti-inflammatory effects when given at lower doses (7.5-30 mg/week). In vitro, methrotrexate inhibits neutrophil chemotaxis, macrophage IL-1 synthesis and basophil histamine release. It has been used extensively for treatment of rheumatoid arthritis and psoriasis. In a small randomized, double-blind, crossover trial reported in 1988, methotrexate was found to decrease the need for systemic steroids and to improve symptoms in patients with steroid-dependent asthma. Subsequently, (as of mid-1997), ten additional randomized, double-blind, placebo-controlled studies of methotrexate in steroid-dependent asthma have been published. In four of these studies, use of methotrexate was associated with a steroid-sparing effect, with stable or improved symptom scores, while in the other six trials the drug had no clear beneficial effect on steroid requirement, symptoms, or pulmonary function. Low-dose methotrexate may be associated with a number of adverse effects, including nausea and vomiting, alopecia, mucosal ulceration, liver function abnormalities and neutropenia, which are generally reversible with discontinuation of therapy. Severe and potentially life-threatening toxic effects, such as hepatic fibrosis, bone marrow suppression, pulmonary fibrosis, and opportunistic infections, may also occur, although they are rare. In summary, methotrexate may reduce steroid requirements in some steroid-dependent asthma patients, but it has not been beneficial in the majority of controlled trials. Given its potential for significant toxicity, methotrexate should be reserved for selected patients who fail to respond to other available therapies. Close monitoring for adverse effects is essential. GoldGold salts are commonly used in the treatment of rheumatoid arthritis. Gold has a number of anti-inflammatory effects relevant to asthma, including inhibition of IgE-mediated release of histamine and LTC4 from mast cells and basophils, inhibition of leukotriene synthesis concomitant with stimulation of prostanoid formation in alveolar macrophages, and inhibition of mediator-induced airway smooth muscle contraction. Parenteral and oral gold preparations have been used in Japan as treatment of asthma for many years. Several small uncontrolled series have supported the efficacy of gold salts in the treatment of asthma. In addition, four randomized, placebo-controlled trials, all involving small numbers of patients, have been published. In one of two studies involving intramuscular gold sodium thiomalate, gold therapy was associated with clinical improvement and lower asthma symptom scores. More recently, two double-blind, placebo-controlled trials demonstrated that the oral gold compound, auranofin, reduced steroid requirements and improved symptoms and pulmonary function in steroid-dependent asthmatics, and decreased airway hyperreactivity in mild, nonsteroid-requiring asthmatics. Gold therapy may be associated with proteinuria, diarrhea, eczema, urticaria, and stomatitis. Clinical experience with gold salts as treatment for asthma is limited in North America; the proper place for this form of therapy remains to be defined. Cyclosporine AThe fungal cyclic polypeptide cyclosporine A protects against rejection of allografts by inhibiting the activation of T lymphocytes. Cyclosporine A acts by disrupting signal transduction leading to transcription of lymphocyte genes, including cytokines IL-2, IL-3, IL-4, IL-5, and TNF. Cyclosporine A also has multiple inhibitory effects on activation of and mediator release by other inflammatory cells, including mast cells, basophils, eosinophils, monocytes-macrophages and neutrophils. It has been used to treat various inflammatory and immunologic disorders, including psoriasis, nephrotic syndrome, and inflammatory bowel disease. Based on the recognition that activated T cells play a key role in driving asthmatic airway inflammation, cyclosporine A has been evaluated recently as therapy for steroid-dependent asthma. In two of three randomized, controlled trials, cyclosporine A reduced steroid requirements and improved pulmonary function compared to placebo. However, treatment with cyclosporine A was associated with a number of adverse effects, including hypertrichosis, decreased renal function, hypertension, paresthesias, tremor, gingival hypertrophy, and minor infections. Although the drug was discontinued due to adverse effects in only a small proportion of asthma patients studied, the unfavorable toxicity profile of cyclosporine A precludes its use in most asthma patients. Development of an inhaled formulation of the drug may change this situation in the future. Newer, less toxic cyclosporine-like drugs are also being developed. New Directions in Anti-Inflammatory TherapyA whole range of novel approaches to asthma therapy is currently under investigation. These new agents target specific cells, cytokines, adhesion molecules, and mediators involved in the pathogenesis of asthma. Some of them, such as monoclonal antibodies directed against CD4 or IgE, have shown encouraging results in early-phase clinical trials. Many other classes of agents are in preclinical development. These include monoclonal antibodies to IL-4 and IL-5, and an antagonist of TNF-a. Monoclonal antibodies to specific adhesion molecules expressed on endothelial cells, epithelial cells and eosinophils (selectins, ICAM, VCAM, and integrins) effectively block key features of the inflammatory response in animal models of asthma. Other potentially useful agents in early phases of investigation include inhibitors of mast cell tryptase, antagonists of neurokinin receptors, and antibodies to or other inhibitors of chemokines or their receptors. SummaryMajor advances have been made in understanding the inflammatory pathogenesis of asthma. As a result, the focus of treatment has now shifted to blocking and reversing airway inflammation. Major changes in drug therapy include greater emphasis on the use of inhaled corticosteroids and the development of a new class of agents, the antileukotrienes. Continued progress in understanding the pathobiology of asthma should result in additional therapeutic gains. References1. McFadden ER Jr, Gilbert IA. Asthma. N Engl J Med 1992; 321:1517-21 2. Guidelines for the diagnosis and management of asthma. Expert Panel Report II. Bethesda, Md: National Institutes of Health, 1997. NIH publication no. 97-4051 3. Holgate S. Mediator and cytokine mechanisms in asthma. Thorax 1993; 48:103-9 4. Barnes PJ. Mechanisms of action of glucocorticoids in asthma. Am J Respir Crit Care Med 1996; 154:S21-7 5. Haahtela T, Jarvinen M, Kava T, et al. Comparison of a beta2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991; 325:388-92 6. Haahtela T, Jarvinen M, Kava T, et al. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med 1994; 331:700-5 7. Wasserman SI. Immunopharmacological profile of nedocromil sodium. Allergy Proc 1995; 16:67-71 8. Schudt C, Tenor H, Hatzelmann A. PDE isoenzymes as targets for anti-asthma drugs. Eur Respir J 1995; 8:1179-83 9. Smith LJ. Leukotrienes in asthma. the potential therapeutic role of antileukotriene agents. Arch Int Med 1996; 156:2181-89 10. Israel E, Rubin P, Kemp JP, et al. The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Ann Int Med 1993; 119:1059-66 11. Spector SL, Smith LJ, Glass M, et al. The effects of 6 weeks of therapy with ICI 204,219, a leukotriene D4-receptor antagonist, in subjects with bronchial asthma. Am J Respir Crit Care Med 1994; 150:618-23 12. Israel E, Cohn J, Dube L, et al. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. JAMA 1996; 275:931-36 13. Liu MC, Dube LM, Lancaster J, and the Zileuton Study Group. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter study. J Allergy Clin Immunol 1996; 98:859-71 |
||||||||||||||||||||||||||||||||||||||||
 |
||
|
||
|
||
|
||
|